The principal objectives of the proposed work are to use linkage studies, in silico cloning, and the isolation of novel genes expressed in cartilage, to identify the disease genes in osteochondrodysplasias of unknown etiology. Transgenic mouse models will be generated to elucidate both the etiology and structural/biochemical basis of specific osteochondrodysplasia phenotypes. Through these studies, we will identify the determinants of normal function for the disease genes and their products. The specific experimental goals of the proposed work are: 1. Definition of osteochondrodysplasia loci and disease genes As families are identified by outreach efforts and by referral to the International Skeletal Dysplasia Registry, a combination of candidate gene and genome-wide markers will be used to determine the chromosomal locations, and subsequently the identities, of novel osteochondrodysplasia disease genes; 2. Identification of new candidate disease genes for osteochondrodysplasias. We will mine our human fetal cartilage cDNA library for novel, cartilage-specific cDNA clones as a complement to the linkage studies. The library will also serve as a source of candidate disease genes for collaborative efforts both within and beyond the subproject; 2. Generation of mouse models for the osteochondrodysplasias. The goal of these studies is to create unique mutations in genes known to play a role in cartilage biology to reveal novel osteochondrodysplasia phenotypes. Over the short term, the accomplishment of the goals of this study will directly benefit families with the conditions under study in providing earlier and more specific diagnosis (including prenatal diagnosis), and thereby improved management and care. Over the longer term, the features of the structure and expression of each gene, as well as the nature of the defects that produce each disease, may suggest rational approaches to therapy. Finally, these studies will then be integrated into a more complete understanding of the biology of the chondrocyte and the elements that define the architecture and function of the cartilage extracellular matrix.